What is the pathophysiology of primary, secondary, and tertiary hyperparathyroidism and how are calcium and vitamin D metabolism related to these disorders?

Pathophysiology of Hyperparathyroidism and Calcium-Vitamin D Correlation

Normal Calcium-PTH-Vitamin D Axis

PTH is released within seconds when the calcium-sensing receptor on parathyroid glands detects hypocalcemia, initiating a cascade that raises serum calcium through three mechanisms: stimulating renal 1-α-hydroxylase to convert 25(OH)D to active 1,25(OH)₂D (which increases intestinal calcium absorption), increasing renal calcium reabsorption while decreasing phosphate reabsorption, and mobilizing calcium and phosphate from bone. 1

• The biologically active PTH molecule is an 84-amino acid peptide with a plasma half-life of only 2-4 minutes, though C-terminal fragments persist 5-10 times longer and accumulate in kidney disease 1
• FGF23, secreted by osteocytes in response to high phosphate, PTH, or 1,25(OH)₂D, counterbalances PTH by increasing renal phosphate excretion and inhibiting 1-α-hydroxylase 1
• The parathyroid glands themselves express both the vitamin D receptor and 1-α-hydroxylase enzyme, allowing local formation of 1,25(OH)₂D that directly suppresses PTH synthesis 2

Primary Hyperparathyroidism

Primary hyperparathyroidism is characterized by elevated serum calcium with inappropriately normal or elevated PTH levels, typically caused by parathyroid adenoma, and represents the most common cause of hypercalcemia. 3

• The biochemical signature is hypercalcemia + elevated PTH + low-normal phosphorus (phosphate is low because PTH increases renal phosphate excretion) 4
• Vitamin D deficiency commonly coexists with primary hyperparathyroidism and exacerbates the condition; vitamin D supplementation can be safely provided with careful monitoring of serum calcium and urinary calcium excretion 5
• Parathyroidectomy is indicated when: symptoms are present, age ≤50 years, serum calcium >1 mg/dL above upper limit of normal, osteoporosis, creatinine clearance <60 mL/min/1.73 m², nephrolithiasis, nephrocalcinosis, or hypercalciuria 3

Secondary Hyperparathyroidism

Secondary hyperparathyroidism develops as a compensatory response to chronic hypocalcemia or hyperphosphatemia, most commonly from chronic kidney disease or vitamin D deficiency, and is distinguished by elevated PTH with low-normal or low calcium and elevated phosphorus. 1, 3

Pathophysiology in CKD

• PTH begins rising once GFR falls below 60 mL/min/1.73 m² due to: (1) reduced renal 1-α-hydroxylase activity causing 1,25(OH)₂D deficiency and decreased intestinal calcium absorption, (2) phosphate retention stimulating PTH secretion and inhibiting 1-α-hydroxylase, and (3) impaired PTH clearance 1, 6
• The biochemical signature is elevated PTH + low-normal or low calcium + elevated phosphorus 4
• Reduced 1,25(OH)₂D levels impair suppression of the parathyroid gene, leading to progressive parathyroid hyperplasia 1
• C-terminal PTH fragments accumulate in kidney disease, causing standard PTH assays to overestimate biologically active PTH 1

Pathophysiology in Vitamin D Deficiency

• 25(OH)D levels <30 ng/mL reduce intestinal calcium absorption, triggering compensatory PTH elevation even with normal kidney function 7, 8
• Vitamin D deficiency is present in 47-76% of CKD stage 3-4 patients, aggravating secondary hyperparathyroidism 7
• In patients with normal kidney function and adequate 25(OH)D levels, insufficient dietary calcium intake (typically <1,200 mg/day) can cause secondary hyperparathyroidism that resolves with calcium supplementation 600 mg twice daily 8

Tertiary Hyperparathyroidism

Tertiary hyperparathyroidism occurs when prolonged secondary hyperparathyroidism causes autonomous parathyroid hyperplasia with nodular transformation, resulting in hypercalcemia despite correction of the underlying stimulus. 1, 6

• This represents a transition from compensatory to autonomous PTH secretion, typically after years of uncontrolled secondary hyperparathyroidism in dialysis patients 1
• The biochemical signature shifts from secondary (low calcium) to primary-like (high calcium), but with markedly elevated PTH (often >800-1,000 pg/mL) and elevated phosphorus 1, 4
• Nodular parathyroid glands develop downregulated vitamin D receptors, requiring higher doses and longer treatment duration (12-24 weeks) to achieve PTH suppression with medical therapy 1
• Parathyroidectomy becomes necessary when PTH remains >800 pg/mL with refractory hypercalcemia and/or hyperphosphatemia despite 3-6 months of optimized medical therapy 7, 4

Critical Calcium-Vitamin D-PTH Interactions

The vitamin D/PTH axis operates through negative feedback: PTH stimulates renal 1,25(OH)₂D production, which then suppresses PTH synthesis both systemically (via increased intestinal calcium absorption) and locally within parathyroid cells (via vitamin D receptor activation). 1, 2

• Vitamin D deficiency breaks this feedback loop by reducing intestinal calcium absorption (stimulating PTH) and removing direct vitamin D receptor-mediated PTH suppression 6, 2
• In CKD, loss of functional renal mass prevents adequate 1,25(OH)₂D production despite elevated PTH, perpetuating the hyperparathyroid state 1
• Hyperphosphatemia in CKD independently stimulates PTH secretion while simultaneously inhibiting 1-α-hydroxylase, creating a vicious cycle 1
• The calcium-phosphorus product must be maintained <55 mg²/dL² to prevent vascular calcification; uncontrolled hyperphosphatemia with vitamin D therapy dramatically increases this product and cardiovascular mortality 1, 7

Target PTH Ranges by CKD Stage

PTH targets are stage-specific and intentionally above normal range in advanced CKD to maintain appropriate bone turnover and prevent adynamic bone disease. 7

• CKD Stage 3 (GFR 30-59): target PTH 35-70 pg/mL 7
• CKD Stage 4 (GFR 15-29): target PTH 70-110 pg/mL 7
• CKD Stage 5/dialysis (GFR <15): target PTH 150-300 pg/mL 1, 7
• Suppressing PTH to normal range (<65 pg/mL) in dialysis patients causes adynamic bone disease with increased fracture risk and impaired calcium-phosphate buffering capacity 1, 7, 4

Common Pitfalls in PTH Assay Interpretation

• Different PTH assay generations measure varying combinations of full-length PTH and C-terminal fragments, causing remarkable inter-laboratory variation in reported values 1
• Guidelines should be applied with caution and assay-specific reference ranges must be used, as a single PTH value may have different clinical implications depending on the assay used 1
• Trend monitoring is more reliable than absolute cutoff values when assessing response to therapy 1